Efficacy and safety of co‐crystal of tramadol‐celecoxib (CTC) in acute moderate‐to‐severe pain after abdominal hysterectomy: A randomized, double‐blind, phase 3 trial (STARDOM2)

Abstract Background STARDOM2 is a randomized, double‐blind, phase 3 trial evaluating the efficacy and safety of co‐crystal of tramadol‐celecoxib (CTC)—a first‐in‐class analgesic co‐crystal comprising racemic tramadol hydrochloride and celecoxib in a supramolecular network that modifies their pharmacokinetic properties—for the management of acute postoperative pain (NCT03062644; EudraCT:2016–000593‐38). Methods Patients with moderate‐to‐severe pain following abdominal hysterectomy were randomized 2:2:2:2:2:1 to oral CTC 100 mg (rac‐tramadol hydrochloride 44 mg/celecoxib 56 mg) twice daily (BID); CTC 150 mg (66/84 mg) BID; CTC 200 mg (88/112 mg) BID; immediate‐release tramadol 100 mg four times daily (QID); celecoxib 100 mg BID; or placebo, for 5 days. The primary endpoint was the sum of pain intensity differences over 0–4 h (SPID0–4). Key secondary endpoints were rescue medication use within 4 h, 50% response rate at 4 h, and safety/tolerability. Results Of 1355 patients enrolled, 1138 were randomized (full analysis set) and 1136 treated (safety analysis set). In the prespecified gatekeeping analysis of SPID0–4, CTC 200 mg was not superior to tramadol but showed non‐inferior efficacy (p < 0.001) that was sustained throughout the 120‐h period, despite a 5‐day cumulative tramadol administration of 880 mg with CTC 200 mg BID versus 2000 mg with tramadol 100 mg QID. Treatment‐emergent adverse events (TEAEs) and severe TEAEs were less common with CTC 200 mg versus tramadol. Treatment‐related TEAEs were 14.4% with CTC 200 mg and 23.6% with tramadol. Conclusions Although the study did not meet its primary endpoint, CTC 200 mg showed a clinically relevant improvement in overall benefit/risk profile versus tramadol alone, with considerably lower cumulative opioid exposure. Significance In the randomized, double‐blind, phase 3 STARDOM2 trial—in acute moderate‐to‐severe pain after abdominal hysterectomy—the novel co‐crystal of tramadol‐celecoxib (CTC) 200 mg BID was superior to placebo and non‐inferior to tramadol 100 mg QID. Although superiority to tramadol was not reached, CTC 200 mg BID exposed patients to lower cumulative opioid (tramadol) doses than tramadol (100 mg QID) alone, with fewer treatment‐emergent adverse events. CTC 200 mg thus has a clinically relevant improved benefit/risk profile compared with tramadol alone.


Inclusion criteria
Patients who met all of the following criteria were included in the study: 1. Female patients ≥18 years old on the day of consent.
2. Willing and able to provide informed consent.
3. Scheduled to have a total or subtotal abdominal hysterectomy under general anaesthesia via a Pfannenstiel incision.
4. The elective procedure (total or subtotal hysterectomy with or without salpingo-oophorectomy) had to be for benign conditions within 28 days of screening. Patients with stage 0 carcinoma in situ of cervix, endometrial hyperplasia, or clinically staged 1A or 1B endometrial cancer were allowed to participate.
5. American Society of Anesthesiology physical status of I or II.
6. Women of childbearing potential had to use highly effective methods of contraception throughout the study.
7. Good general health as judged by investigators on the basis of medical history and physical examination.
8. Willingness to comply with the study procedures and requirements.
Additional inclusion criteria after surgery: 1. Abdominal hysterectomy completed without any immediate complication.
2. Tolerating oral fluids, no uncontrolled nausea/vomiting, and ready to take oral analgesia.
3. Patient was alert and calm, and spontaneously paid attention to the caregiver, e.g. Richmond Agitation-Sedation Scale = 0. This had to be measured within a maximum of 30 hours after end of surgery and patients could only be randomized on the day after surgery, after cessation of postoperative analgesia.

Exclusion criteria
Patients who met any of the following criteria were excluded from the study: 1. Any abnormal laboratory value that was clinically significant (in the opinion of the investigator) that would compromise the safety of the patient in the study. 13. Treated regularly with opioid analgesic or NSAIDs within 30 days prior to screening or who had received a long-acting NSAID within 3 days prior to the start of the surgery.
14. Incapable of complying with the protocol.
15. Epidural or spinal anaesthesia or infiltration of the wound with an infusion of a local anaesthetic agent was not allowed. A single perioperative dose was allowed.
16. History or ongoing chronic pelvic inflammatory disease or painful endometriosis.
17. History of advanced gynaecological cancers.
Additional exclusion criteria after surgery: 1. Serious complication during surgery and up to randomization, including: a. Postoperative primary and secondary bleed that could not be controlled.
b. Patients in whom the abdominal hysterectomy surgery was not completed as planned.
2. Any factors that may, in the investigator's opinion, have affected compliance with the protocol.
3. Clinical need for antiemetics (apart from standard perioperative practice as defined in the protocol) or any other medication that is prohibited.
4. Received any analgesic medication other than perioperative analgesia as described in the protocol.
5. Any concerns that renal function had deteriorated, for example, a laboratory parameter, profound hypotension, poor urine output, or excessive bleeding during surgery. midazolam 1-2 mg and temazepam 5-10 mg orally) • IV induction with propofol • Isoflurane, sevoflurane, or desflurane without nitrous oxide • A single perioperative dose of local anaesthetic for wound infiltration was allowed. Lidocaine (lignocaine), articaine, and mepivacaine were allowed • Bolus doses of IV fentanyl or morphine were permitted, as needed • IV induction with paracetamol up to 1 g • Non-opioid analgesic medication (except intravenous paracetamol) • Opioid analgesic medication: In general, not allowed (including IV sufentanil and remifentanil) except intravenous morphine and fentanyl as detailed above During intake of study drug: • Serotonergic drugs, including SSRIs and SNRIs • Tricyclic antidepressants

Additional secondary endpoints
Sum of pain intensity differences over 0-12, 0-24, 0-48, 0-72, 0-96, and 0-120 hours The sum of pain intensity differences (SPID) was calculated at 12, 24, 48, 72, 96, and 120 hours based on PI-VAS values with last observation carried forward (LOCF) imputation applied. Statistical analyses of the secondary SPID endpoints were performed using the same analysis of covariance (ANCOVA) model as in the primary analysis of the primary endpoint SPID0-4 for the full analysis set and per-protocol analysis set.

Treatment response (30% and 50%)
Patients with a reduction of pain, as assessed on the PI-VAS scale, of 50% from 0-4 hours were defined as 50% responders at 4 hours.
For treatment response parameters, odds ratios and corresponding two-sided 95% confidence intervals for treatment differences were calculated, along with p values for two-sided tests of the null hypothesis.

Time to perceptible pain relief and time to meaningful pain relief
Patients used their electronic diaries to record time to perceptible pain relief (PPR) and time to meaningful pain relief (MPR). Time was measured from the time of the first intake of study medication. The patient stopped the timer for the first time as soon as they noted that their pain was not getting worse and had possibly improved.
This was the time to PPR.
Once the patient began to feel clearly less pain, they stopped the timer for a second time. This was the time to MPR.
Time to PPR and time to MPR were summarized using Kaplan-Meier estimates and were analysed via time-to-event methodology using Cox proportional hazards models.

Rescue medication use
The following variables were derived from rescue medication (RM) use data: RM use in the first 4 hours, average number of RM use occasions per 24 hours, average dose of RM per 24 hours, and time to first RM use.
Average RM use and average dose (mg) of RM were summarized using descriptive statistics. Average dose of RM per 24 hours was analysed further using an ANCOVA model with treatment and QPI as fixed effects, centre (with pooling of centres applied) as a random effect, and pre-dose (0 hours) as a covariate.  random effect, and pre-dose (0 h) pain intensity as a covariate.

Supplementary Tables and Figures
g OR for observing a 50% response at 4 h for CTC versus tramadol; p value from one-sided test (lower limit) of the null hypothesis that the OR is ≤1.
h OR for using ≥1 dose of rescue medication during the first 4 h for CTC versus tramadol; p value from one-sided test (upper limit) of the null hypothesis that the OR is ≤1.
ANCOVA, analysis of covariance; CI, confidence interval; CTC, co-crystal of tramadol-celecoxib; diff. LS means, difference in least-squares means; FAS, full analysis set; N, number of patients in analysis set; n1, number of patients used for analysis in CTC treatment arm; n2, number of patients used for analysis in placebo or tramadol arm; OR, odds ratio; PPAS, per-protocol analysis set; QPI, qualifying pain intensity; SPID0-4, sum of pain intensity differences over 0-4 h.     null hypothesis that the difference of means is zero]. These data were analysed using an analysis of covariance model with treatment and QPI at randomization (moderate or severe) as fixed effects, centre as random effect, and pre-dose (0 h) pain intensity as a covariate. b HR: CTC 100, 150, or 200 mg versus placebo/tramadol/celecoxib (95% CI) [p value -two-sided test of no difference for testing null hypothesis that the HR is 1]. These data were analysed using a Cox proportional hazard model with treatment and QPI at randomization (moderate or severe) as fixed effects, centre as random effect, and pre-dose (0 h) pain intensity as a covariate.

Fig. S1
Study design. AE, adverse event; BID, twice daily; CTC, co-crystal of tramadol-celecoxib; FU, follow-up; QID, four times daily; R, randomization; V, Visit. The telephone icon indicates that the visit could be conducted by telephone. aV5 and V6 were performed at the study site for patients participating in pharmacokinetic sampling. and (c) celecoxib plasma concentration data (mean ± SD). CTC, co-crystal of tramadol-celecoxib; SD, standard deviation.